WO2008075483A1 - Ｌ－アミノ酸の製造法 - Google Patents

Ｌ－アミノ酸の製造法 Download PDF

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WO2008075483A1
WO2008075483A1 PCT/JP2007/067387 JP2007067387W WO2008075483A1 WO 2008075483 A1 WO2008075483 A1 WO 2008075483A1 JP 2007067387 W JP2007067387 W JP 2007067387W WO 2008075483 A1 WO2008075483 A1 WO 2008075483A1
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gene
strain
seq
amino acid
plasmid
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PCT/JP2007/067387
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English (en)
French (fr)
Japanese (ja)
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Yoshihiko Hara
Hiroshi Izui
Jun Nakamura
Ranko Nishi
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Ajinomoto Co., Inc.
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Priority to EP07806828.5A priority Critical patent/EP2100957B1/en
Priority to BRPI0721063-9A priority patent/BRPI0721063B1/pt
Priority to CN200780047446.8A priority patent/CN101563453B/zh
Publication of WO2008075483A1 publication Critical patent/WO2008075483A1/ja
Priority to US12/478,049 priority patent/US8058035B2/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0008—Oxidoreductases (1.) acting on the aldehyde or oxo group of donors (1.2)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/001—Oxidoreductases (1.) acting on the CH-CH group of donors (1.3)

Definitions

  • the present invention relates to a method for producing L amino acids such as L glutamic acid using microorganisms.
  • L-glutamic acid is industrially useful as a seasoning raw material, and other L-amino acids are used as additives for animal feeds, health food ingredients, amino acid infusions, and the like.
  • wild-type bacteria wild strains
  • auxotrophic strains derived from wild strains
  • L-glutamic acid is produced by fermentation using a so-called coryneform bacterium belonging to the genus Brevibacterium, Corynebacterium, and Microbataterum, or an L-glutamic acid-producing bacterium or a mutant thereof.
  • Non-Patent Document 1 Other methods for producing L-glutamic acid by fermentation using other strains include methods using microorganisms such as Bacillus genus, Streptomyces genus, Penicillium genus (see, for example, Patent Document 1), Syudumonas genus, Earth Methods using microorganisms such as Lacta, Serratia, Candida (see, for example, Patent Document 2), microorganisms such as Bacillus, Syudomonas, Serratia, Aerobacter aerogenes (currently Enterobacter aerogenes) Methods (for example, see Patent Document 3), methods using mutant strains of Escherichia coli (for example, see Patent Document 4), and the like are known.
  • a method for producing L-glutamic acid using a microorganism belonging to the genus Klebsiella, Ervinia, Pantothea, or Enteropacter is also disclosed (for example, see Patent Documents 5 to 7).
  • SDH succinate dehydrogenase
  • Non-patent Document 2 a succinate dehydrogenase-deficient strain is also known in Escherichia coli belonging to the intestinal bacterial group (Non-patent Document 2), but its relationship with L-glutamic acid production has not been known.
  • Patent Document 1 U.S. Pat.No. 3,220,929
  • Patent Document 2 U.S. Pat.No. 3,563,857
  • Patent Document 3 Japanese Patent Publication No. 32-9393
  • Patent Document 4 JP-A-5-244970
  • Patent Document 5 JP 2000-106869 Koyuki
  • Patent Document 6 Japanese Unexamined Patent Publication No. 2000-189169
  • Patent Document 7 Japanese Unexamined Patent Publication No. 2000-189175
  • Patent Document 8 U.S. Pat.No. 5,168,056
  • Patent Document 9 U.S. Pat.No. 5,776,736
  • Patent Document 10 U.S. Pat.No. 5,906,925
  • Patent Document 11 Japanese Patent Publication No. 7-121228
  • Patent Document 12 Japanese Unexamined Patent Publication No. 2000-189175
  • Patent Document 13 European Patent Application Publication No. 771879
  • Patent Document 14 European Patent Application Publication No. 0952221
  • Patent Document 15 European Patent Application Publication No. 1078989
  • Non-Patent Document 1 Kunihiko Akashi et al. Amino Acid Fermentation, Academic Publishing Center, 195-215, 198 6
  • Non-Patent Document 2 J Gen Microbiol. 1978 Jul; 107 (1): 1-13
  • An object of the present invention is to provide a bacterium capable of efficiently producing an L amino acid such as L-glutamic acid and a method for efficiently producing an L amino acid using the bacterium.
  • the present invention is as follows.
  • a microorganism having L-amino acid-producing ability and modified so that succinate dehydrogenase activity and ⁇ -ketognoletarate dehydrogenase activity are reduced is cultured in a medium, and L-amino acid is produced and accumulated in the medium or in the cell body.
  • Succinate dehydrogenase activity or ⁇ -ketoglutarate dehydrogenase by reducing the expression level of the gene encoding succinate dehydrogenase or ⁇ -ketoglutarate dehydrogenase or destroying these genes The method, wherein the activity is reduced.
  • succinate dehydrogenase is one or more genes selected from sdhA gene, sdhB gene, sdhC gene and sdhD gene.
  • microorganism is a bacterium belonging to the family Enterobacteriaceae, or a coryneform bacterium.
  • amino acid power is an L amino acid biosynthesized using glutamic acid or L-glutamic acid as a precursor.
  • L-amino acid power is selected from L-arginine, L-proline, L-ornithine, L-citrulline, and L-glutamine.
  • FIG. 1 is a diagram showing the structure of a helper plasmid RSF-Red-TER.
  • FIG. 2 shows the construction of helper plasmid RSF-Red-TER.
  • the method of the present invention uses a microorganism having L amino acid-producing ability and modified so that succinate dehydrogenase activity and ⁇ -ketoglutarate dehydrogenase activity are reduced.
  • L is a method for producing amino acids.
  • the microorganism used in the present invention can be obtained by using a microorganism having L amino acid-producing ability as a parent strain and modifying the microorganism so that succinate dehydrogenase and ⁇ -ketoglutarate dehydrogenase activities are reduced.
  • the microorganism used in the present invention is modified so that the succinate dehydrogenase and ⁇ -ketoglutarate dehydrogenase activities are reduced.
  • the obtained microorganism can be obtained as a parent strain by imparting or enhancing L-amino acid-producing ability.
  • the microorganism used in the present invention may inherently have L-amino acid-producing ability, or may have been given L-amino acid-producing ability by breeding using a mutation method or recombinant DNA technology. But it's okay.
  • the “L amino acid-producing ability” means having the ability to produce L-amino acid to the extent that it can be recovered from the cells or the medium when the microorganism used in the present invention is cultured in the medium. Preferably, it has the ability to produce a larger amount of L amino acid than a wild strain or an unmodified strain cultured under the same conditions.
  • L-amino acids include L-lysine, L-glutamic acid, L-threonine, L-valine, L-leucine, L-isoleucine, L-serine, L-aspartic acid, L-asparagine, L-gnoletamine, L-arginine, L-cysteine (cystine), Examples include L-methionine, L-phenylalanine, L-tryptophan, L-tyrosine, L-glycine, L-alanine, L-proline, L-ornitine, L-citrulline, and L-homoserine, but L-glutamic acid or L-glutamic acid as a precursor L Particularly preferred are amino acids such as L-glutamic acid, L-gnoretamine, L-proline, L-arginine, L-ornitine, and L-sitorelin.
  • microorganisms used in the production method of the present invention include microorganisms belonging to the family Enterobacteriaceae such as bacteria belonging to the genus Escherichia, Pantoea, and Enteropacter, Corynebacterium glutamicum, Brevibaterium. Powers including coryneform bacteria such as Mentum and Bacillus bacteria such as Bacillus subtilis are not limited to these.
  • the “coryneform bacterium” has been conventionally classified into the genus Brevibaterium, but includes bacteria that are currently classified into the genus Corynebatarum (Int. J. Syst. Bacteriol. , 41, 255 (1991)), and also contains bacteria of the genus Brevibaterium which are very closely related to the genus Corynebataterium. Examples of such coryneform bacteria include the following.
  • Corynebacterium 'samoaminogenes Corynebacterium fifciens Corynebacteria no, Kiuris
  • ATCC American 'type ⁇ Culture ⁇ Collection
  • the microorganisms belonging to the family Enterobacteriaceae used in the present invention belong to the genus Escherichia, Enterobata, Pantoea, Klebsiella, Serratia, Enorevinia, Sanoremonella, Morganella, etc., and L amino acids As long as it has the ability to produce, there is no particular limitation. Specifically, those belonging to the family Enterobacteriaceae can be used according to the classification described in the NCBI (National Center for Biotechnology Information) database (http: ⁇ www.ncbi.nlm.nih.gov/htbin-post/Taxonomy / wgetorg?
  • the parent strain of the bacterium belonging to the genus Escherichia is not particularly limited. And others (Neidhardt, FC et al., Escherichia coli and Salmonella Typhimurium, Ameri can Society for Microbiology, Washington D.C., 1029 table 1) can be used. Among them, for example, Escherichia coli is mentioned. Specific examples of Escherichia coli include Escherichia coli W31 10 (ATC C 27325) and Escherichia coli MG 1655 (ATCC 47076) derived from the prototype wild type K12 strain.
  • Pantoea bacteria, Erbinia bacteria, and Enteropacter bacteria are categorized as ⁇ proteobacteria and are taxonomically closely related (J Gen Appl Microbiol 1997 355_ «5, International Journal of systematic Bacteriology, Oct. 1997, p1061-1067).
  • some bacteria belonging to the genus Enteropacter have been reclassified as Pantoea agglomerans or Pantoea dispersa by DNA-DNA hybridization experiments and the like.
  • the bacteria belonging to the genus Elvinia are reclassified as Pantoea ananas and Pantoea's Stuarti. (See International Journal of Systematic Bacteriology Jan 1993; 43 (1) ⁇ ⁇ ⁇ 162-173).
  • bacteria belonging to the genus Enteropacter include Enterobacter agglomerans, Enterobacter aerogenes, etc. 0, specifically, European Patent Application Publication No. 952221
  • the representative strains of the genus Enteropacter include the Enteropactor 'Agglomerans ATCC 12287 strain.
  • Pantoea ananatis Pantoea stewartii
  • Pantoea agglomerans Pantoea citrea
  • Specific examples include the following strains:
  • Pantoea Ananatis AJ 13355 (FERM BP-6614) (European Patent Application Publication No. 0952221)
  • Pantoea Ananatis AJ 13356 (FERM BP-6615) (European Patent Application Publication No. 0952221) These strains have been re-established in Pantoea Ananatis by the analysis of the nucleotide sequence of 16S rRNA, as described above, as described in European Patent Application Publication No. 0952221 as Enteropactor-Agglomerans. It is classified.
  • Examples of the genus Erwinia include Erwinia 'Amiguchi Bola' and Erwinia 'power rotobora.
  • Examples of the Klebsiella bacterium include Klebsiella' planticola. Specifically, the following strains are mentioned.
  • L-amino acid biosynthetic enzymes whose expression is enhanced may be used alone or in combination of two or more.
  • imparting properties such as auxotrophy, analog resistance, and metabolic regulation mutation may be combined with enhancement of biosynthetic enzymes.
  • an auxotrophic mutant, an analog-resistant strain, or a metabolically controlled mutant having L amino acid-producing ability the parent strain or wild-type strain is subjected to normal mutation treatment, that is, irradiation with X-rays or ultraviolet rays, or N Methyl-N'—Nitrowe N Ditrosoguanidine etc.
  • normal mutation treatment that is, irradiation with X-rays or ultraviolet rays, or N Methyl-N'—Nitrowe N Ditrosoguanidine etc.
  • mutant strains obtained by treating with the above, etc. it is possible to obtain by selecting those exhibiting auxotrophy, analog resistance, or metabolically controlled mutations and having the ability to produce L amino acids.
  • An L-amino acid-producing bacterium can also be obtained by enhancing the enzyme activity of an L-amino acid biosynthesis enzyme by genetic recombination.
  • Examples of a method for imparting or enhancing L-glutamic acid-producing ability by breeding include a method of modifying so that expression of a gene encoding an enzyme involved in L-glutamic acid biosynthesis is enhanced.
  • L Enzymes involved in glutamate biosynthesis include, for example, glutamate dehydrogenase (gdhA), glutamine synthetase (g 1 ⁇ ), glutamate synthase (gltAB), isocitrate dehydrogenase (icdA), aconite hydratase (acnA, acnB), and ken Acid synthase (gltA), phosphoenolpyruvate strength lupoxylase (ppc), pyruvate carboxylase, pyruvate dehydrogenase (ace EF, lpdA), pyruvate kinase (pykA, pykF), phosphoenolpyruvate synthase (ppsA
  • a DNA fragment containing these genes is used as an appropriate plasmid, for example, a plasmid vector containing at least a gene responsible for the replication and replication function of the plasmid in a microorganism. This is achieved by introducing the amplified plasmid introduced into the gene, or by making multiple copies of these genes by joining, transferring, etc. on the chromosome, and introducing mutations into the promoter region of these genes. (See the international pamphlet W095 / 34672).
  • the promoter for expressing these genes only needs to function in coryneform bacteria.
  • the promoter may be a proper promoter or the promoter of the gene itself to be used, or may be modified.
  • the expression level of the gene can also be controlled by selecting a promoter that functions strongly in coryneform bacteria, or by bringing the 3510 region of the promoter closer to the consensus sequence.
  • Microorganisms modified so as to enhance the expression of citrate synthase gene, isocitrate dehydrogenase, pyruvate dehydrogenase gene, and / or glutamate dehydrogenase gene by the method as described above include WO00 / 18935 pamphlet, European patent Examples thereof include microorganisms described in Japanese Patent Application Publication No. 1010755.
  • the modification for imparting L-glutamic acid-producing ability may be carried out by reducing or eliminating the activity of the enzyme that catalyzes the reaction that generates the other compound by branching the biosynthesis pathway of L-glutamic acid.
  • Enzymes that catalyze reactions that branch off from the biosynthetic pathway of L-glutamic acid to produce compounds other than L-Daltamate include isocitrate lyase, acetohydroxyacid synthase, acetolactic acid synthase, acetyl acetyl transferase, lactic acid Examples include dehydrogenase, glutamate decarboxylase, 1 pyrroline 5-carboxylate dehydrogenase, and acetyl CoA hydride (WO2006 / 057450).
  • the activity of the enzyme as described above can be reduced or eliminated by a method similar to the method for reducing the succinate dehydrogenase activity and ⁇ -ketoglutarate dehydrogenase activity described below.
  • D-xylulose-5-phosphate phosphoketolase and / or funolectoose 6-phosphate phosphoketolase examples include a method of introducing a gene encoding fructose-6-phosphate phosphoketolase (referred to collectively as phosphoketolase).
  • microorganisms with increased phosphoketolase activity include the following microorganisms: Brevibacterium ratatofamentum ATCC13869 A sucA (pVK9_x),
  • L-gnoretamic acid The ability to produce L-gnoretamic acid is defined as 6 phosphodanoleconate dehydratase activity or 2 keto
  • microorganisms having increased 6-phosphodarconate dehydratase activity and 2-ketose 3 deoxy-6 phosphodarconate aldolase activity include the microorganisms disclosed in JP-A-2003-274988.
  • L-glutamic acid-producing ability can also be imparted by amplifying the yhfK gene, which is an L-glutamic acid excretion gene (WO2005 / 085419).
  • the L-glutamic acid-producing microorganism used in the present invention has the ability to accumulate L-glutamic acid in an amount exceeding the saturation concentration of L-glutamic acid in a liquid medium when cultured under acidic conditions (hereinafter referred to as acidic conditions).
  • acidic conditions a liquid medium when cultured under acidic conditions
  • Microorganisms having the ability to accumulate L-glutamic acid in the present invention For example, by obtaining a strain with improved resistance to L-glutamic acid in a low pH environment by the method described in European Publication No. 1078989, the ability to accumulate an amount of L-glutamic acid exceeding the saturation concentration is imparted. be able to.
  • microorganisms capable of accumulating L-glutamic acid under acidic conditions include Pantoea Ananatis AJ13355 (FERM BP-6614), AJ13356 (FERM BP-6 615), AJ1360 Zhu (FERM BP-7207) (see European Patent Application Publication No. 0952221), SC17sucA strain, SC17sucA / RSFCPG + pSTVCB strain, NP106 strain, NA Zhu, and the like.
  • Pantoea Ananatis AJ13355 is a strain that was isolated from the soil of Soda, Shizuoka Prefecture, as a strain that can grow on a medium containing L-dartamic acid and a carbon source at low pH.
  • AJ13356 is a strain in which the a KGDH-E1 subunit gene (sucA) of AJ 13355 strain is deleted.
  • Pantoair Ananatis AJ13355 and AJ13356 shares were established on February 19, 1998, at the Institute of Biotechnology, National Institute of Advanced Industrial Science and Technology (now the National Institute of Advanced Industrial Science and Technology, patent product deposit center, address zip code 305 -8566 Deposited at Ibaraki Prefecture Tsukuba Sakai Higashi 1-chome 1-Chuo 6) under the accession numbers FERM P-16644 and FERM P-16645 respectively. It was transferred to an international deposit under the Budapest Treaty on 11 January 2011 and has been given the accession numbers FERM BP-6614 and FERM BP-6615.
  • L-gnoretamic acid-producing bacteria of Pantoea ananatis include bacteria belonging to the genus Pantoea that have lost ketogonoletate dehydrogenase (a KGDH) activity or have reduced a KGDH activity.
  • Such strains include the aforementioned AJ13356 strain and SC17sucA (US Pat. No. 6,596,517), which is a sucA gene-deficient strain derived from the SC17 strain, which was also selected as a mucous low-producing mutant.
  • the SC17sucA strain was granted the private number AJ417.
  • Patent Biological Deposit Center (address zip code 305-8566 Tsukuba Sakaihigashi, Ibaraki Pref. No. 6) is deposited under the accession number FERM BP-08646.
  • the SC17sucA / RSFCPG + pSTVCB strain contains, in addition to the SC17sucA strain, a citrate synthase gene (gltA), a phosphoenolpyruvate carboxylase gene (ppsA), and a glutamate dehydrogenase gene (gdhA) derived from Escherichia coli.
  • a citrate synthase gene gltA
  • ppsA phosphoenolpyruvate carboxylase gene
  • gdhA glutamate dehydrogenase gene
  • AJ1360 Zhu was selected from the SC17sucA / RSFCPG + pSTVCB strain as a strain resistant to high concentrations of L-glutamic acid at low pH.
  • the NP106 strain is a strain obtained by removing the plasmid RSFCPG + pSTVCB from AJ1360 vermilion.
  • a method for imparting resistance to an organic acid analog or a respiratory inhibitor, or a method for imparting sensitivity to a cell wall synthesis inhibitor may be mentioned.
  • a method of imparting monofluoroacetic acid resistance Japanese Patent Laid-Open No.
  • resistant bacteria include the following strains.
  • microorganisms capable of producing L-glutamine include bacteria with enhanced glutamate dehydrogenase activity, bacteria with enhanced glutamine synthetase (glnA) activity, and bacteria with disrupted dullaminase gene (European patent application) (Publication Nos. 1229121 and 1424398). Enhancement of glutamine synthetase activity can also be achieved by destruction of glutamine adenyltransferase (glnE) or PII regulatory protein (glnB).
  • glnE glutamine adenyltransferase
  • glnB PII regulatory protein
  • strains belonging to the genus Escherichia and having a mutant glutamine synthetase in which the tyrosine residue at position 397 of glutamine synthetase is substituted with another amino acid residue can be exemplified as suitable L-glutamine-producing bacteria (US patent application). (Publication No. 2003-0148474).
  • Brevibacterium 'flavum AJ 11573 (FERM P-5492; JP 56-161495) Brevibacterium flavum AJ 11576 (FERM BP-10381; JP 56-161495) Brevibacterium' flavum AJ12212 (FERM P -8123; JP-A 61-202694)
  • Examples of microorganisms having L proline-producing ability include bacteria that retain ⁇ daltamyl kinase that has been desensitized to feedback inhibition by L proline and bacteria that have weakened the L proline degradation system.
  • a method for modifying bacteria using DNA encoding ⁇ -glutamyl kinase desensitized to feedback inhibition by L-proline is described in Dandekar, AM, Uratsu, SL, J. Bacteriol., 170, 12, 5943-5 (1988). Is disclosed.
  • Examples of a method for obtaining a bacterium with a weakened L-proline degradation system include a method for introducing a mutation that reduces enzyme activity into the proline dehydrogenase gene.
  • bacteria having L proline-producing ability examples include Escherichia coli NRRL B-12403 strain and NRRL B-12404 strain (UK Patent 2075056), V PM B-8012 strain (US Patent Publication 2002-0058315), and Retains plasmid variants disclosed in German Patent No. 3127361 and plasmid variants disclosed in Bloom FR et al. (The 15th Miami winter symposium, 1983, p.34) And the like.
  • microorganisms having L-proline-producing ability preferably include Escherichia coli 702 strain (VKPMB-8011), which is a strain resistant to 3,4-dehydroxyproline and azatidine-2-carboxylate.
  • 702ilvA strain VKPMB-8012 strain
  • Escherichia coli that has enhanced the activity of the protein encoded by b2 682 and b2683, bl242 or b3434 gene (JP 2002 — No. 300874).
  • L-proline-producing bacteria of coryneform bacteria include DL-3, 4-dehydroproline resistant strains (F ERM BP-1219, US Pat. No. 4,224,409), and citrate synthase activity is 1.4 times higher than its parent strain. Examples include strains that have increased (FERM P-5332, FERM P_5333, FERM P_5342, FERMP-534 3 Patent No. 1426823), and strains that have been given acetic acid requirement (FERM P-5931).
  • Examples of microorganisms capable of producing L-mouth isine include, for example, Escherichia coli H-9068 strain (ATCC 21530) and H-907 0 which are resistant to 4-azaleucine or 5,5,5-trifluoroleucine. Strain (FERM BP-4704) and H-9072 (FERM BP-4706) (US Pat. No. 5,744,331), and Escherichia coli (European patent) that retains isopropyl malate synthase that has been desensitized to feedback inhibition by L-mouth isine 1067191), Escherichia coli AJ11478 (US Pat. No.
  • L-tissue isin producing strains of coryneform bacteria include 2 thiazolealanine and ⁇ -hydroxyleucine resistant strains (JP-A 8-266295), valine analog resistant strains (JP-A 63-24839 2), Phosphorus auxotrophic strain (Japanese Patent Publication No. 38-4395), S— (2 aminoethyl) L Cystein ( ⁇ C) resistant strain (Japanese Patent Publication No. 51-37347), phenylalanine, valine, isoleucine auxotrophic strain (Japanese Patent Publication No. 54- 36233).
  • Escherichia coli JM15 strain (US Pat. No. 6,218, 168) transformed with a cysE gene allele encoding serine acetyltransferase desensitized to feedback inhibition
  • Escherichia coli W3110 strain (US Pat. No. 5,972,663) overexpressing a gene that codes for a protein that excludes cytotoxic substances
  • Escherichia coli (JP-A-11-155571) with reduced cysteine desulhydrase activity.
  • Amplified Cysteine Leglon Transcription Activator Encoded by cysB Gene Examples include Escherichia coli W3110 strain (WO01 / 27307).
  • Examples of microorganisms capable of producing L isoleucine include mutant strains of Escherichia bacteria exhibiting 6-dimethylaminopurine resistance (Japanese Patent Laid-Open No. 5-304969), L isoleucine hydroxamate, tiisoleucine, and DL ethionine.
  • a mutant strain resistant to arginine hydroxamate Japanese Patent Laid-Open No. 5-130882
  • a recombinant strain in which a threonine deaminase gene and a acetohydroxy acid synthase gene are amplified Japanese Patent Laid-Open No. 2-458, Japanese Patent Laid-Open No. 2-42988, Kaihei 8-47397.
  • L-isoleucine-producing bacteria of coryneform bacteria include coryneform bacteria (JP 2001-169788) in which a brnE gene that encodes a branched-chain amino acid excretion protein is amplified, and protoplast fusion with L-lysine-producing bacteria.
  • Coryneform bacterium with the ability to produce isoleucine JP-A-6-74293
  • coryneform bacterium with enhanced homoserine dehydrogenase JP-A 62-91193
  • JP-A 62-195293 A-ketomalone resistant strain
  • Japanese Patent Laid-Open No. 61-15695 Japanese Patent Laid-Open No. 61-15695
  • methyllysine resistant strain Japanese Patent Laid-Open No. 61-15696.
  • L-valine can be imparted, for example, by increasing the activity of L-valine synthase encoded by the ilvGMEDA operon, particularly the acetate hydroxylate synthase encoded by the ilvG gene (special Fairness 02-748418).
  • the L-valine synthase may be released from feedback inhibition by L-parin.
  • the ability to produce L-norin can also be conferred by reducing the expression of the acetate lactate synthase III gene (ilvIH gene).
  • L-parin-producing ability can be imparted by imparting amino acid analog resistance to bacteria.
  • bacteria examples include mutant strains (FERM P-1841, FERM, which require L-isoleucine and L-methionine requirement and have B1 life on D-ribose, purine nucleoside or pyrimidine ribonucleoside, for example. P-5556; Japanese Patent Laid-Open No. 53-025034) and mutants showing resistance to polyketides (FERM P-9325; Patent No. 01934507).
  • Examples of L-valine-producing bacteria also include a mutant strain having an aminoacyl t-RNA synthetase mutation (US Patent No. 5,658,766).
  • E. coli VL1970 having a mutation in the ileS gene encoding isoleucine tRNA synthetase can be used.
  • E. coli VL197 0, June 24, 1988, Lucian ⁇ National ⁇ Collection ⁇ Industrial 'My It has been deposited with Kroonoreganisms (VKPM) (1 Dorozhny proezd., 1 Moscow 117545, Russia) under the accession number VKPM B-4411.
  • a mutant strain (WO96 / 06926) that requires lipoic acid for growth and / or lacks H + -ATPase can be used as a parent strain.
  • L-parin-producing bacteria of coryneform bacteria include strains modified so that expression of a gene encoding an enzyme involved in L-valic acid biosynthesis is enhanced.
  • the enzyme involved in L-valinate biosynthesis include ilvBNC operon, ie, acetohydroxy acid synthase encoding ilvBN and isomeroreductase (ilvCX International Publication Pamphlet WO 00-50624).
  • ilvBNC operon is regulated by operon expression by L-noline and / or L-isoleucine and / or L-soutine isine, it is necessary to release the categorization to release the suppression of the expression by L-valine produced. Is desirable.
  • L Aranin The microorganism having an ability to produce, for example, H + -ATP ase activity coryneform bacterium (Appl Microbiol Biotechnol 2001 Nov; 57 (4).: 534_40) deficient Ya Asuparagin acid ⁇ over decarboxylase gene And coryneform bacteria (Japanese Patent Application Laid-Open No. 07-163383).
  • Microorganisms having L-arginine-producing ability include ⁇ -methylmethionine, ⁇ -fluo-feruylalanin, D-arginine, arginine hydroxamic acid, AEC (S— (2-aminoethyl) monocysteine), a —methylserine, / 3 Examples thereof include Escherichia coli mutant strains having resistance to -2-chelalanine or sulfaguanidine (see JP-A-56-106598). Further, Escherichia coli 237 strain (Russian patent application No.
  • L-arginine biosynthetic enzymes include N-acetyl glutamate synthase (argA), N-acetyl tiltyl phosphate reductase (argC), ornithine acetyl transferase (argj), N-acetyl.
  • Glutamate kinase argB
  • Acetyl ornithine transaminase argD
  • Acetyl ornithine deacetylase argE
  • Ornithine strength rumoyltransferase argF
  • Argininosuccinate synthase argG
  • Argininosuccinate lyase argH
  • carAB ruvamoyl phosphate synthase
  • argA N-acetyl glutamate synthase
  • the L-arginine-producing bacteria of coryneform bacteria are not particularly limited as long as they have L-arginine-producing ability, but coryneform bacteria wild strains such as sulfa drugs, 2-thiazolalanine or ⁇ -amino ⁇ -hydroxyvaleric acid, etc. Coryneform bacteria resistant to drugs; 2 In addition to thiazolealanin resistance, L-histidine, L-proline, L-threonine, L-isoleucine, L-methionine or L-tryptophan-requiring coryneform bacteria No.
  • coryneform bacteria resistant to ketomalonic acid, fluoromalonic acid or monofluoroacetic acid JP 57-18989
  • coryneform bacteria resistant to argininol JP 62-24075
  • And coryneform bacteria JP-A-2-86995 resistant to X guanidine (X is a fatty acid or fatty chain derivative).
  • the coryneform bacterium having L-arginine-producing ability is a mutant strain resistant to 5-azauracil, 6-azauracil, 2-thiouracil, 5-fluorouracil, 5-bromouracil, 5-azacytosine, 6-azacytosine and the like; arginine hydroxamate , 2 mutants resistant to thiouracil, mutations resistant to arginine hydroxamate and 6-azauracil Strain (Japanese Patent Laid-Open No. 49-126819); a mutant strain resistant to histidine analogs or tributophan analogs (Japanese Patent Laid-Open No.
  • coryneform bacteria having L-arginine-producing ability include the following strains.
  • L-citrulline and L-ornithine share the same biosynthetic pathway as L-arginine, and include N-acetylglutamate synthase (argA), N-acetyltiltamyl phosphate reductase (argC), ornithine. Providing these abilities by increasing the enzyme activities of acetyltransferase (argj), N-acetylglutamate kinase (argB), acetyl olnitine transaminase (argD), and acetyl olnitine deacetylase (argE). Power S can be. (International Publication 2006-35831 Pamphlet)
  • microorganisms having L-lysine-producing ability include L-lysine having L-lysine-producing ability.
  • Gin analogue resistant strain or metabolic control mutant strain specifically, Escherichia coli AJ11442 strain (FERM BP-1543, NRRL B-12185; see JP-A-56-18596 and US Pat. No. 4,434,170) And Escherichia coli VL61 Zhu (JP 2000-189180 A).
  • Escherichia coli AJ11442 strain (FERM BP-1543, NRRL B-12185; see JP-A-56-18596 and US Pat. No. 4,434,170)
  • Escherichia coli VL61 Zhu JP 2000-189180 A
  • WC196 strain see International Publication No. 96/1 7930
  • the WC196 strain was bred by conferring AEC (S- (2-aminoethyl) cysteine) resistance to the W3110 strain derived from Escherichia coli K-12.
  • This strain was named Escherichia coli AJ13069, and on December 6, 1994, the National Institute of Biotechnology, National Institute of Advanced Industrial Science and Technology (currently the National Institute of Advanced Industrial Science and Technology, Patent Biodeposition Center, T 305-8566 Japan) No. 1 in Tsukuba, Higashi, Ibaraki, Kokubu, Ibaraki Prefecture, No. 6), deposited under the deposit number FERM P-14690, transferred to an international deposit under the Budapest Treaty on September 29, 1995, and deposited under the deposit number FERM BP- 5252 is granted.
  • AEC S- (2-aminoethyl) cysteine
  • AEC S- (2-aminoethyl) cystine (hereinafter abbreviated as “AEC”) resistant mutant strain (Brevibacterium) Umm 'Ratatofamentum AJ11082 (NRRL B-11470), etc .: JP-B 56-1914, JP-B 56-1915, JP-B 57-14157, JP-B 57-14158, JP-B 57 -30474, JP-B 58-10075, JP-B 59_4993, JP-B 61-35840, JP-B 62-24074, JP-B 62-36673, JP-B 5-11958 Gazettes, Japanese Patent Publication No.
  • a microorganism to which L-lysine-producing ability is imparted can also be obtained by increasing the enzyme activity of the L-lysine biosynthesis system. Such an increase in enzyme activity can be achieved by increasing the copy number of the gene encoding the enzyme in the cell and modifying the expression regulatory sequence.
  • L-lysine biosynthesis enzymes include dihydrodipicolinate synthase gene (dapA), aspartokinase gene (lysC), dihydrodipicolinate reductase gene (dapB), diaminopimelate decarboxylase gene (lysA), diaminopimelate dehydrogenase gene (ddh) (international publication 96/40934 pamphlet), phosphoenolpyruvate carboxylase gene (ppc) (JP-A-60-87788), aspartate aminotransferase gene ( aspC) (Japanese Patent Publication No.
  • diaminopimerin epimerase gene (Japanese Patent Laid-Open No. 2003-135066), aspartate semialdehyde dehydrogenase gene (asd) (International Publication No. 00/61723 pamphlet)
  • Diaminovimelic acid pathway enzyme gene such as homoaconitic acid hydrator Gene Gene enzymes etc. (JP 2000- 157276 JP), etc. aminoadipic acid pathway and the like.
  • the Aspartokinase III gene should not be subject to feedback inhibition by L-lysine.
  • the lysC gene modified so as not to receive such feedback inhibition can be obtained by the method described in US Pat. No. 5,932,453.
  • microorganisms having L-lysine-producing ability may have reduced or deficient activity of enzymes that catalyze reactions that produce compounds other than L-lysine, and enzyme activities that function negatively in L-lysine production.
  • enzymes include homoserine dehydrogenase, lysine decaenase.
  • Lupoxylase (cadA, ldcC), malicenzyme, and the strains in which the activity of the enzyme is reduced or deficient are disclosed in International Publication No. W095 / 23864, WO96 / 17930 pamphlet, W02 005/010175 pamphlet, etc. It is described in.
  • a microorganism having an ability to produce L-tribtophan is preferably a bacterium in which one or more of anthranilate synthase activity, phosphodariserate dehydrogenase activity or tryptophan synthase activity is enhanced. Since anthranilate synthase and phosphodariserate dehydrogenase are subject to feedback inhibition by L tryptophan and L-serine, respectively, the enzyme activity can be enhanced by retaining a desensitized mutant enzyme.
  • the anthranilate synthase gene (trpE) and / or the phosphodalylate dehydrogenase gene (serA) is mutated so as not to receive feedback inhibition, and the obtained mutant gene is transformed into bacteria.
  • a bacterium that retains the desensitizing enzyme can be obtained. More specifically, such a bacterium is a plasmid PGH5 (international) that has a mutant serA encoding a desensitized phosphodalylate dehydrogenase in Escherichia coli SV164, which holds a desensitized anthranilate synthase.
  • Examples include transformed strains obtained by introducing Public Publication No. 94/08031 pamphlet).
  • the ability to produce L-tryptophan can also be imparted by introducing a recombinant DNA containing a tryptophan operon.
  • a recombinant DNA containing a tryptophan operon include Escherichia coli into which a tryptophan operon containing a gene encoding a desensitized anthranilic acid synthase has been introduced (JP 57-71397, JP 62-244382). US Pat. No. 4,371,6 14).
  • trpBA tryptophan synthase-encoding gene
  • Tryptophan synthase consists of ⁇ and / 3 subunits and is encoded by trpA and trpB, respectively.
  • L tryptophan-producing ability may be imparted by introducing trpR coding for tryptophan operon repressor, or by introducing a mutation that reduces repressor activity into trpR.
  • US Pat. No. 4,371,614, International Publication No. WO2005 / 0 56776 pamphlet [0079]
  • malate synthase, isocitrate triase, isocitrate dehydrogenase kinase / phosphatase operon (ace operon), or bacteria with enhanced expression of operon are also suitable.
  • L Tribtophan producing bacteria Specifically, the ace operon promoter is not repressed by the repressor iclR, or such a bacterium that is desired to be derepressed is achieved by disrupting the iclR gene. be able to.
  • a strain containing Escherichia coli AGX17 (pGX44) [NRRL B-12 263] strain having a characteristic of L phenylalanin and L-tyrosine, and a plasmid containing a tryptophan operon AGX6 (pGX50) aroP CNRRL B — 12264] strain carrying pGX50 (see US Pat. No. 4,371,614).
  • Coryneform bacteria having the ability to produce L-tryptophan include corynebataterium 'glutamicum AJ12118 (FERM BP-478 patent 01681002), which is resistant to sulfaguanidine, and a coryneform bacterium introduced with a tryptophan operon ( JP-A-S63240794) and coryneform bacteria into which a gene encoding shikimate kinase derived from coryneform bacteria has been introduced (JP-A 0199 4749) can be used.
  • L-tryptophan, L-phenylalanine, and L-tyrosine are all aromatic amino acids and share a biosynthetic system, and the gene encoding an aromatic amino acid biosynthetic enzyme is deoxya.
  • Rabinohepturonic acid phosphate synthase (aroG), 3-dehydroquinate synthase (aroB), shikimate dehydrogenase (aroE), shikimate kinase (aroL), 5-enolate pyruvine shikimate 3-phosphate Synthase (aroA) and chorismate synthase (aroC).
  • aroG Rabinohepturonic acid phosphate synthase
  • aroB 3-dehydroquinate synthase
  • aroE shikimate dehydrogenase
  • aroL shikimate kinase
  • 5-enolate pyruvine shikimate 3-phosphate Synthase (aroA) and chorismate
  • Microorganisms capable of producing L-phenylalanine include Escherichia coli AJ12739 (tyrA :: TnlO, tyrR) (V PM B_8197), which lacks tyrA and tyrR, and E. which retains the mutant pheA34 gene.
  • coli HW1089 ATCC 55371) (US Pat.No. 5,354,672)
  • E. coli MWEC101-b KR8903681
  • E.coli NRRL B-12141, NRRL B-12145, NRRL B-12146 and NRRL B-12147 US Pat.
  • Strains belonging to the genus Escherichia such as 4,407,952), but are not limited thereto.
  • coli ⁇ coli K-12 [W3110 (tyrA) / pPHAB] (FERM BP-3566)
  • E. coli K-12 [W3110 (tyrA) / pPHAD] (FERM BP— 12659)
  • the coryneform bacterium producing felanuaranin includes corynebataterium daltamicam BPS-13 strain (FERM BP-1777, 77 (FERM BP-) with reduced phosphoenolpyruvate carboxylase or pyruvate kinase activity. 2062) and 78 (FERM BP-2063) (European Patent Publication No. 331145 JP 02303495), tyrosine-requiring strain (JP 05049489), etc.
  • Preferable microorganisms having L-threonine-producing ability include microorganisms belonging to the family Enterobacteriaceae with enhanced L-threonine biosynthesis enzymes.
  • the genes encoding L-threonine biosynthetic enzymes include aspartokinase III gene (lysC), aspartate semialdehyde dehydrogenase gene (asd), aspartokinase I gene (thrA) encoded by the thr operon, Examples include homoserine kinase gene (thrB) and threonine synthase gene (thrC).
  • the inside of Katsuko is an abbreviation for the gene. Two or more of these genes may be introduced.
  • L-threonine biosynthetic genes may be introduced into Escherichia bacteria with suppressed threonine degradation! /.
  • bacteria belonging to the genus Escherichia in which threonine degradation is suppressed include, for example, TD H6 strain lacking threonine dehydrogenase activity (Japanese Patent Laid-Open No. 2001-346578).
  • TD H6 strain lacking threonine dehydrogenase activity Japanese Patent Laid-Open No. 2001-346578.
  • L-threonine-producing bacteria it is desirable to modify the L-threonine biosynthetic gene so that it is not subject to feedback inhibition by L-threonine.
  • the thrA, thrB, and thrC genes constitute the threonine operon.
  • the threonine operon forms an attenuator structure, and the expression of the threonine operon inhibits isoleucine and threonine in the culture medium. In response, expression is suppressed by attenuation. This modification can be achieved by removing the leader region or the attenuation region of the attenuation region.
  • a unique promoter exists upstream of the threonine operon, it may be replaced with a non-natural promoter (see pamphlet of WO98 / 04715), or the expression of a gene involved in threonine biosynthesis is A threonine operon as governed by a repressor and promoter may be constructed.
  • a threonine operon as governed by a repressor and promoter may be constructed.
  • a strain resistant to a-amino- ⁇ -hydroxyvaleric acid (AHV) should be selected. Is also possible.
  • the threonine operon modified so that it is not subject to feedback inhibition by L-threonine has an increased copy number in the host, or is linked to a strong promoter and the expression level is improved. It is preferable.
  • the increase in copy number can be achieved by transferring the threonine operon on the genome by transposon, Mu-phage, etc. in addition to amplification by plasmid.
  • L-threonine biosynthetic enzyme it is also preferable to enhance the genes involved in glycolysis, TCA cycle, respiratory chain, genes controlling gene expression, and sugar uptake genes.
  • these genes that are effective for L-threonine production include transhydronase (pntAB) gene (European patent 733712), phosphoenolpyruvate carboxylase gene (p mark C) (International publication 95/06114 pamphlet) , Phosphoenolpyruvate Examples thereof include a synthase gene (pps) (European Patent No. 877090), and a pyruvate carboxylase gene (International Publication No. 99/18228, European Application No. 1092776) of a coryneform bacterium or a Bacillus bacterium.
  • a gene conferring resistance to L-threonine a gene conferring resistance to L-homoserine, or to confer L-threonine resistance and L-homoserine resistance to the host.
  • genes that confer resistance include the rhtA gene (Res. Microbio 1. 154: 123-135 (2003)), the rhtB gene (European Patent Application Publication No. 0994190), and the rht C gene (European Patent Application Publication No. 1013765). No. specification), yfiK, yeaS gene (European Patent Application Publication No. 1016710 specification).
  • the methods described in European Patent Application Publication No. 0994190 and International Publication No. 90/04636 can be referred to.
  • Examples of microorganisms capable of producing L-threonine include Escherichia coli VKPM B-3996 (see US Pat. No. 5,175,107). This VKPM B-3996 share was registered with Russian National Collection of Industrial Microorganisms (VKPM), GNU Genetika on November 19, 1987 in Russian National 'Collection of Industrial Microorganisms (VKPM), GNU Genetika. Deposited under 3996.
  • This VKP M B-3996 strain is also a threonine in the broad vector plasmid pAY C32 (see Chistorerdov, ⁇ .
  • Escherichia coli B-5318 strain (see European Patent No. 0593792) can also be exemplified as a bacterium imparted with a suitable L-threonine-producing ability.
  • B-5318 shares were registered with Russian National Collection of Industrial Microorganisms (VKPM), GNU Gnetika on 19 November 1987 under the registration number VKPM B-5318. Originally deposited. Also this VKPM B-5318 The strain is a non-isoleucine-requiring strain, and is a threonine operon that lacks the intrinsic transcriptional regulatory region of the lambda phage downstream of the N-terminal portion of the temperature-sensitive C1 repressor, PR promoter and Cro protein.
  • the L-amino acid-producing bacterium used in the present invention has a gene that is involved in sugar uptake, sugar metabolism (glycolysis), and energy metabolism in addition to a gene encoding a specific biosynthetic enzyme. May be.
  • genes involved in sugar metabolism include genes encoding glycolytic enzymes and sugar uptake genes.
  • the glucose 6-phosphate isomerase gene (pgi; International Publication No. 01/02542 pamphlet), Phosphoenolpyruvate synthase gene (pps; published in European application 877090), phosphodalcomtase gene (pgm; published internationally 03/04598 pamphlet), fructose niphosphate aldolase gene (ftp; published internationally 03/04664 pan) Frets), pyruvate kinase gene (pykF; WO 03/008609 pamphlet), transaldolase gene (talB; WO 03/008611 pamphlet), fumarase gene (fom; WO 01/02545 pamphlet) , Phosphoenolpyruvate synthase gene (pps; published European application 877090 pamphlet), non-PTS sucrose removal Inclusive gene gene (csc; European
  • genes involved in energy metabolism include transhydrogenase genes (pntAB;
  • the microorganism used in the present invention is a microorganism having an L-amino acid-producing ability as described above, and modified so that succinate dehydrogenase activity and ⁇ -ketoglutarate dehydrogenase activity are reduced.
  • ⁇ 1 2> Decrease in succinate dehydrogenase activity and ⁇ -ketoglutarate dehydrogenase activity
  • “enzyme activity is reduced” means that succinate dehydrogenase activity and ⁇ -ketoglutarate dehydrogenase activity are low compared to an unmodified strain such as a parent strain or a wild strain. Including disappearing completely! /.
  • Succinate dehydrogenase (hereinafter sometimes referred to as “SDH”) is an enzyme that reversibly catalyzes the following reaction of EC: 1.3.99.1.
  • the SDH activity means an activity that catalyzes this reaction.
  • SDH is composed of three or four subunit structural forces, depending on the microbial species.
  • SDH is composed of the following subunits (the gene name that encodes the subunit in Katsuko), and depending on the species, membrane anchor protein is encoded by sdhC alone or by sdhC and sdhD! / There is something.
  • SDHA flavoprotein subunit (sdhA)
  • SDHB Fe_S protein suounit sdhB
  • SDHC membrane anchor protein (sdhC)
  • SDHD membrane anchor protein (sdhD)
  • the SDH subunit complex may have both SDH and fumarate reductase activities.
  • the SDH subunit complex of coryneform bacteria has both SDH and fumarate reductase activities (WO2005 / 021770).
  • SDH activity can be confirmed by measuring the reduction of 2,6-dichloroindophenol (DCIP) as an index.
  • DCIP 2,6-dichloroindophenol
  • genes encoding each of the SDH subunits and the operons containing them may be collectively referred to as “genes encoding SDH”.
  • the gene encoding SDH of coryneform bacteria includes, for example, the sdh operon of Corynebaterum glutamicum (GenBank accession No. NCgl0359 (sdhC) NCgl0360 (sdhA) NCg 10361 (sdhB)), and the sdh operon of Brevibaterium flavum (JP 2005-095169, EP1672077A1) are disclosed.
  • ⁇ -ketoglutarate dehydrogenase (hereinafter sometimes referred to as “a _KGDH” ⁇ ) activity means that a-ketoglutarate (2-oxodaltaric acid) is oxidatively decarboxylated and succinylated.
  • Lou CoA the reaction to produce (succin y preparative CoA) means an activity to catalyze.
  • the above reaction consists of a-GDH (Elo: a-ketoglutarate dehydrogenase, EC: 1.2.4.2), dihydrolipoamide S-succininotransferase (E2o: dihydrolipoamide-S-succinyltransfera se; EC: 2.3.
  • dihydrolipoamide dehydrogenase Catalyzed by three enzymes E3: dihydrolipoamide dehydrog enase; EC: 1.8.1.4. That is, these three types of subunits catalyze the following reactions, and the activity that catalyzes the combined reaction of these three reactions is called a-KGDH activity! Confirmation of a-KGDH activity is measured by the force S measured according to the method of Shiio et al. (Isamu Shio and Kyoko Ujigawa-Takeda, Agric. Biol. Chem., 44 (8), 1897-1904, 1980).
  • NAD protein N6- (lipoyl) lysine + NADH +
  • ⁇ -KGDH is also called oxoglutarate dehydrogenase or 2-oxoglutarate dehydrogenase.
  • sucA and sucB of Pantoea ananatis and the sucC gene present downstream are shown in SEQ ID NOs: 7 to 11 .
  • sucA, sucB and sucC genes encoding Escherichia coli ⁇ -KGDH are disclosed in GenBank NP.415254 and NP_415255, respectively.
  • the Elo subunit is encoded by the odhA gene (also referred to as sucA gene, registered as NCgll084 of GenBank Accession No. NC_003450), and the E3 subunit is encoded by the lpd gene (GenBank Accession No. Y16642).
  • the E2o subunit is encoded by the odhA gene as a bifunctional protein along with the Elo subunit (see Usuda et al., Microbiology 1996 142, 334 7-3354), or a GenBank Accession other than the odhA gene. It is presumed to be encoded by a gene registered as NCgl2126 of No. NC_003450. Therefore, in the present invention, the odhA gene may encode E2o together with a force that is a gene encoding the Elo subunit.
  • nucleotide sequence of the odhA gene of Brevibateratum 'Ratatofmentum' and the amino acid sequence of the Elo subunit are shown in SEQ ID NOs: 12 and 13, respectively.
  • nucleotide sequence of NCgl2126 of GenBank Accession No. NC.003450 and the amino acid sequence of the E2o subunit encoded by the same sequence are shown in SEQ ID NOs: 14 and 15, respectively.
  • genes encoding each of the ⁇ -KGDH subunits and gene clusters containing them may be collectively referred to as “genes encoding ⁇ -KGDH”. Reducing each enzyme activity can be performed, for example, by the following method.
  • the genes encoding SDH or ⁇ -KGDH are used to modify these genes per cell relative to the parental or wild type.
  • the enzyme activity per molecule of the enzyme protein may be reduced or lost.
  • the number of enzyme protein molecules can be reduced by reducing the expression level of the gene encoding the enzyme.
  • the decrease in the gene expression level includes a decrease in the transcription level of mRNA transcribed from the gene and a decrease in the translation amount of the mRNA.
  • the gene encoding SDH to be modified may be one or more of the genes encoding any of the subunits of SDH, or the entire operon. Mutations may be introduced into genes encoding units (SDHA, SDHB, SDHC, SDHD).
  • the gene encoding a-KGDH to be modified may be one or more of the genes encoding any of the subunits of a-KGDH, or the entire gene cluster.
  • a gene encoding the Elo subunit (sucA or odhA) or a gene encoding the E2o subunit (sucB) is preferable.
  • each remains The variant of the gene is a homologue of each gene, for example, the chromosome of a microorganism such as Enterobacteriaceae or coryneform bacterium, and the nucleotide sequence of SEQ ID NO: 1, 7, 12, 14, 73, or 81, for example.
  • SDH a protein having any one of the amino acid sequences of SEQ ID NOs: 2-4, 6, 74-76, 78-80, and as subunits of ⁇ -KGDH, SEQ ID NOs: 8-11, 13, Examples include proteins having any of the amino acid sequences 15 and 81, but the codons used differ depending on the bacterial strain, and there may be differences in the base sequence of each gene. These amino acid sequences may encode amino acid sequences containing one or several amino acid substitutions, deletions, insertions, or additions, unless otherwise changed.
  • severeal means, for example,;!-20, preferably 1-; 10, more preferably 1-5.
  • a conservative mutation is a polar amino acid between Phe, T rp and Tyr when the substitution site is an aromatic amino acid, and between Leu, lie and Val when the substitution site is a hydrophobic amino acid.
  • it is an acid, it is between Gln and Asn.
  • it is a basic amino acid, it is between Lys, Arg, and His.
  • it is an acidic amino acid, it is an amino acid having a hydroxyl group between Asp and Glu.
  • conservative mutations are conservative substitutions, which are considered conservative substitutions: Ala to Ser or Thr substitution, Arg to Gln, His or Lys substitution, Asn to Glu Gin, Lys, His or Asp substitution, Asp to Asn, Glu or Gin substitution, Cys to Ser or Ala substitution, Gin force to Asn, Glu, Lys, His, Asp or Arg substitution Glu to Asn, Gin, Lys or Asp, Gly to Pro, His to Asn, Lys, Gin, Arg or Tyr, lie to Leu, Met, Val or Phe, Substitution from Leu to Ile, Met, Val or Phe, Lys to Asn, Glu, Gln, His or Arg, Met to Ile, Leu, Val or Phe, Phe to Trp, Tyr, Met, lie or Leu substitution, Ser to Thr or Ala substitution, Thr to Ser or Ala substitution, Trp to Phe or Tyr substitution, Tyr to His, Phe or Trp substitution, and , Substitution of Val to Met, lie or Le
  • the variants of each gene include those base sequences or coding regions consisting only of genes having the base sequence of each coding region in the base sequence of SEQ ID NO: 1, 7, 12, 14, 73, 77, or 81. It may be DNA I that hybridizes under stringent conditions with a probe IJ that is complementary to the base sequence, or a probe that can be prepared from the base sequence! /. “Stringent conditions” refers to conditions under which so-called specific hybrids are formed and non-specific hybrids are not formed. For example, DNAs having high homology, for example, DNAs having 80% or more, preferably 90% or more, more preferably 95% or more, further preferably 97% or more, and particularly preferably 99% or more.
  • each other and Haiburidizu, it homologous than low! /, DNA with each other Haiburidizu Shinano! /, conditions, there! / is a condition of washing Rere of typical Southern hybridization Daizeshiyon 6 0. c, 1 X SSC, 0. 1 0/0 SDS, preferably (or, 60 ° C, 0. 1 X SSC, 0. 1% SDS, more preferably, 68.C, 0. 1 X SSC, 0. Examples include conditions of washing once, more preferably 2 to 3 times, at a salt concentration and temperature corresponding to 1% SDS.
  • the length of the probe is a force appropriately selected according to the hybridization conditions. Is from 100 bp to 1 Kbp.
  • gene modification involves deletion of part or all of the gene coding region on the chromosome, or modification of an expression regulatory sequence such as a promoter or Shine-Dalgarno (SD) sequence. Etc. are achieved.
  • expression level of a gene can also be reduced by modifying an untranslated region other than the expression regulatory sequence.
  • the entire gene may be deleted, including sequences before and after the gene on the chromosome.
  • amino acid substitution missense mutation
  • termination codon is introduced (nonsense mutation), or 1 to 2 base addition / deletion is performed.
  • sucA and sucB genes are present upstream of the sdh operon, and by introducing a mutation that reduces the expression level of the sdh operon, the expression levels of the sucA and sucB genes are reduced. Such a mutation is also included in the present invention.
  • modified by gene recombination refers to an expression regulatory sequence of a gene on a chromosome, such as a promoter region, a coding region, or a non-coding region using homologous recombination. This refers to reducing the enzyme activity in the cell by deleting a part or all of the above, or by inserting another sequence into these regions. In the present invention, it is preferable that the gene is modified to such an extent that the gene inactivation is not restored by natural mutation.
  • the modification is such that SDH activity and ⁇ -KGDH activity are decreased, irradiation with X-rays or ultraviolet rays, or normal using a mutation agent such as N-methyl ⁇ 'nitro-N-nitrosoguanidine, etc. It may be modified by mutation treatment.
  • the modification of the expression regulatory sequence is preferably 1 base or more, more preferably 2 bases or more, and particularly preferably 3 bases or more.
  • the deletion region can be any of the ⁇ terminal region, the internal region, and the C-terminal region. It may be the entire code area. Usually, the longer region to be deleted can surely inactivate the gene. Further, it is preferable that the reading frames upstream and downstream of the region to be deleted do not coincide.
  • any region of the gene may be used.
  • the sequence inserted into 1S has a longer direction and can reliably inactivate the gene encoding the enzyme.
  • the sequences before and after the insertion site preferably do not match the reading frame.
  • the other sequence is not particularly limited as long as it reduces or eliminates the function of the enzyme protein, and examples thereof include an antibiotic resistance gene and a transposon carrying a gene useful for L-glutamic acid production.
  • a deletion-type gene that lacks a partial sequence of the gene and is modified so as not to produce a normally functioning enzyme protein is produced.
  • the gene on the chromosome is replaced with the deleted gene.
  • the enzyme protein encoded by the deletion-type gene it has a three-dimensional structure different from that of the wild-type enzyme protein, and its function is reduced or lost. Gene disruption by gene replacement using such homologous recombination has already occurred.
  • a strain resistant to the ⁇ Red gene product for example, Pantoea ananatis SC17 (0) strain
  • SC17 (0) shares were registered with the Russian National Collection of Industrial Microorganisms (VPM), GNU Genetika on 21 September 2005, Russian VN National Collection of Industrial Microorganisms (VPM), GNU Genetika. Deposited under B-9246.
  • Strains with reduced ⁇ -KGDH activity can be obtained by the method (1) described above, or can be obtained by the following method using nutritional requirements.
  • microbial cells were subjected to normal mutation treatment (eg, 250 ⁇ ⁇ / 1111, 30 ° C, 20 minutes) with N-methyl-N, 12-trowel N-trosoguanidine, and then a solid medium. Cultivate above to form colonies. From this, a strain with reduced a-K GDH activity can be isolated by isolating mutant strains that cannot grow on a medium containing L-glutamic acid as a single carbon source and single nitrogen source by the replica method.
  • strains with reduced a-KGDH activity include the following strains.
  • the ⁇ -KGDH activity-reduced strain requires succinic acid for growth due to the decreased supply of succinyucci CoA.
  • succinic acid requirement is restored in double deficient strains of ⁇ -KGDH and SDH (J Gen Microbiol. 1978 Jul; 107 (l): 1-13). Therefore, a strain with reduced ⁇ -KGDH and SDH activity can be obtained by selecting a strain with a restored succinic acid requirement from a strain with reduced ⁇ -KGDH activity S.
  • a strain with reduced a-KGDH activity is plated on a minimal medium containing no succinic acid to form colonies.
  • strains with reduced a-KGDH activity that can grow on minimal medium without succinic acid There is a mutation in the gene that codes for SDH!
  • L-amino acids can be produced by culturing the above microorganisms in a medium, producing and accumulating L-amino acids in the medium or in the cells, and collecting the L-amino acids from the medium or the cells.
  • the medium used for the culture a normal medium containing a carbon source, a nitrogen source, inorganic salts, and other organic micronutrients such as amino acids and vitamins as necessary can be used. Synthetic media or natural media! /, And deviations can be used.
  • the carbon and nitrogen sources used in the medium are those that can be used by the strain being cultured!
  • the carbon source saccharides such as glucose, glycerol, fructose, sucrose, maltose, mannose, galactose, starch hydrolysate, molasses and the like can be used.
  • organic acids such as acetic acid and citrate, ethanol, etc. Alcohols can also be used alone or in combination with other carbon sources.
  • ammonia salts such as ammonia, ammonium sulfate, ammonium carbonate, ammonium chloride, ammonium phosphate, ammonium acetate, and the like can be used.
  • organic micronutrients amino acids, vitamins, fatty acids, nucleic acids, peptone containing these, casamino acids, yeast extracts, soybean protein degradation products, etc. can be used, and nutritional requirements that require amino acids for growth. When using mutants, it is preferable to supplement the required nutrients.
  • inorganic salts phosphates, magnesium salts, calcium salts, iron salts, manganese salts and the like can be used.
  • the culture is preferably carried out by aeration culture at a fermentation temperature of 20 to 45 ° C and a pH of 3 to 9.
  • inorganic or organic acidic or alkaline substances, ammonia gas, etc. can be used for pH adjustment.
  • L amino acid accumulates in the culture solution or in the fungus body.
  • a liquid medium adjusted to conditions where L-glutamic acid is precipitated is used to precipitate L-glutamic acid in the medium.
  • Culture can also be performed to accumulate.
  • the conditions under which L-glutamic acid precipitates are, for example, ⁇ 5.0 to 4.0, preferably pH 4.5 to 4.0, more preferably ⁇ 4.3 to 4.0, and particularly preferably ⁇ 4.0.
  • PH is preferably 5.0 to 4.0, more preferably 4.5 to 4.0, and still more preferably 4.3 in order to achieve both the improvement of the growth of L and the efficient precipitation of L-glutamic acid. It is desirable to be -4.0.
  • the culture at the above pH may be the whole period or a part of the culture.
  • the method for collecting L-amino acid from the culture broth after completion of the culture may be performed according to a known recovery method. For example, it is collected by removing microbial cells from the culture solution and then concentrating crystallization or ion exchange chromatography.
  • L-glutamic acid precipitated in the culture solution can be collected by centrifugation or filtration. In this case, L-glutamic acid dissolved in the medium may be crystallized and then isolated together! /.
  • Trehalose may be added to the medium and cultured.
  • the concentration of trehalose contained in the medium is preferably 0.1 g / L or more, preferably 0.2 g / L or more, more preferably 0.5 g / L or more.
  • coryneform bacteria it is preferable to add 0.5 g / L or more, preferably 0.75 g / L or more, more preferably 2 g / L or more.
  • the trehalose added to the medium may dissolve crystalline trehalose, or may use trehalose contained in the mother liquor after recovering the target substance from the fermentation solution produced in the fermentation process.
  • trehalose in the medium may be produced as a by-product in the fermentation broth according to the present invention.
  • betaine N-methylglycine, N-N-dimethylglycine, NNN-trimethylglycine, [2-Hide mouth kichetil] trimethylmonmonium
  • betaine N-methylglycine, N-N-dimethylglycine, NNN-trimethylglycine, [2-Hide mouth kichetil] trimethylmonmonium
  • Productivity is improved. It is preferable to add 0.1 g / L or more, preferably 0.25 g / L or more, more preferably 0.5 g / L or more.
  • This plasmid can be used in a wide range of hosts with different genetic backgrounds. The reasons are as follows: 1) It has many Gram-negative and Gram-positive bacteria and the RSF1010 broad host range plasmid replicon that can be stably maintained even in plants (Scholz, et al., 1989). Buchanan- Wollaston et al., 1987), 2) The ⁇ Red, gam, bet and exo genes are in the regulation of the PlacUV5 promoter, recognized by many bacterial RNA polymerases (see, for example, Brunschwig, E. et al. and Darzins, A., Gene, 111, 1, 35-41 (199 2); Dehio, M. et al, Gene, 215, 2, 223-229 (1998)), 3) Autoregulator P-lad, And
  • the prn-independent transcription terminator (TrrnB) of the rrnB operon of lacUV5 escherichia coli reduces the basal expression level of the ⁇ Red gene (Skorokhodova, A. Yu et al, Biotekhnologiya (Rus), 5, 3-21 (2004)). Furthermore, the RSF-Red-TER plasmid contains a levansucrase gene (sacB), which allows the plasmid to be recovered from the cells in a medium containing sucrose.
  • sacB levansucrase gene
  • Cells transformed with the RSF-Red-TER helper plasmid are IPTG (isopropyl _ / 3-D-thiogalactopyranoside, ImM) and an appropriate antibiotic (chloramphenicol 25 g / ml or kanamycin 40 g / ml) in LB medium containing a very low growth rates, the efficiency of the lambda Red-mediated recombination ( ⁇ Red-mediated recombination) is extremely low! if observed, (10 8).
  • Pantoea ananatis SC17 strain (US Pat. No. 6,596,517) was introduced by RSF-Red-TER plasmid by electopore positioning. After 18 hours of cultivation, approximately 10 6 transformants were obtained, and up to 10 clones were large in size. Yes, the rest were all very small. After 18 hours of culture, large colonies were about 2 mm and small colonies were about 0.2 mm. Even when the culture was extended to 24 hours, the small colonies continued to grow, and the large colonies continued to grow.
  • One of the large colony Pantoea ananatis mutants B1 live for the expression of all three genes of the ⁇ Red gene (gam, bet and exo) was used for further analysis.
  • RSF-Red-TER plasmid DNA was isolated from one large colony clone and several small colony clones and retransformed into Escherichia coli MG1655 to produce the active product of the Red gene. The ability of the plasmid to be synthesized was examined. Control experiments for Red-dependent integration in the resulting transformants showed that only plasmids isolated from large colony clones resulted in the expression of the ⁇ Red gene required for Red-dependent integration. .
  • the RSF-Red-TER plasmid can induce the expression of the Red gene by the lad gene on the plasmid.
  • Two induction conditions were investigated. In the first group, IPTG (lmM) was added 1 hour before electoral position, and in the second group, IPTG was added at the beginning of the culture for the preparation of electorizable cells. Progeny growth rates of cells carrying RSF-Red-TER from large colony clones were significantly lower than strains without the SC17 plasmid. The addition of IPTG only slightly reduced the growth rate of these cultures. On the other hand, the progenies of small colony clones grow very slowly without the addition of IPTG. did.
  • helper plasmid RSF-Red-TER The construction scheme of the helper plasmid RSF-Red-TER is shown in FIG.
  • the RSFsacBPlacMCS vector was designed.
  • DNA fragments containing the structural part of the cat gene of the PACYC184 plasmid and the sacB gene of Bacillus subtilis were amplified by PCR using the oligonucleotides of SEQ ID NOs: 19, 20, 21, and 22, respectively.
  • Each of these oligonucleotides contains convenient BglII, Sad, Xbal, and BamHI restriction enzyme sites at the 5 'end that are necessary for further cloning. Yes.
  • the obtained 1.5 kb sacB fragment was converted to the Xbal-BamH of the pMW119_Plad vector obtained earlier.
  • This vector describes the pMW118-P lad vector
  • this vector contains a polylinker site from pMW219 instead of the pMW218 plasmid.
  • pMW-P 1 lac adsacBcat contains the PlacUV5-lacI_sacB-cat fragment.
  • pMW_P ladsacBcat was digested with Bglll and the DNA polymerase
  • the 3.8 kb Bglll-Sad fragment of the IsacBcat plasmid was eluted from a 1% agarose gel and ligated to the RSF1010 vector treated with Pstl and Sad.
  • Escherichia coli TG1 was transformed with the ligation mixture and plated on LB medium containing chloramphenicol (50 mg / L). Restriction enzyme analysis was performed on the plasmid isolated from the grown clones to obtain RSFsacB plasmid.
  • the sequences of SEQ ID NOs: 23 and 24 are used.
  • a DNA fragment containing the P lac lac promoter was amplified by PCR using oligonucleotides as primers and the pMW119-P lad plasmid as a saddle type.
  • the resulting 146 bp fragment was Sad
  • PCR using the oligonucleotides of SEQ ID NOs: 27 and 24 as primers and the chromosome of Escherichia coli BW3350 as a saddle was carried out by PCR using the P promoter and Trm lacUV5.
  • a DNA fragment containing the B terminator was amplified. Treat these fragments with Kpnl Connected. Thereafter, a 0.5 kb fragment containing both P and TrmB was obtained by PCR using the oligonucleotides of SEQ ID NOS: 24 and 28 as primers.
  • the obtained DNA fragment was digested with EcoRI, treated with DNA polymerase I Klenow fragment to make blunt ends, cut with BamHI, and ligated with the large Ecll36II_BamHI fragment of RSFsacBPlacMCS vector.
  • the resulting plasmid was named RSF-Red-TER.
  • the pMWl 18- (lattL-Km r _lattR) plasmid was constructed by replacing the MWl 18-attL-Tc-attR (WO2005 / 01017 5) plasmid strength, et al., tetracycline resistance marker gene with the kanamycin resistance gene of the pUC4K plasmid. did. Therefore, P and MW118-attL-Tc-at tR EcoRI-Hindlll large fragment of plasmid was ligated to two fragments of HindIII-PstI of pUC4K plasmid (676 bp) and E coRI-HindIII (585bp). The basic pMW118-attL-Tc_attR was obtained by linking the following four fragments.
  • AttL (sequence) obtained by PCR amplification using primers P1 (SEQ ID NO: 29) and P2 (SEQ ID NO: 30) from the region corresponding to attL of the chromosome of Escherichia coli W3350 (including prophage) Bglll-EcoRI fragment (114 bp) with number 31). These primers contain secondary recognition sites for Bglll and EcoRI.
  • AttR (sequence) obtained by PCR amplification using primers P3 (SEQ ID NO: 32) and P2 (SEQ ID NO: 33) from the region corresponding to attR of the chromosome of Escherichia coli W3350 (including prophage) Pstl-Hindlll fragment (182bp) with number 34). These primers contain secondary recognition sites for Pstl and Hindlll.
  • Bglll-Pstl small fragment (363 bp) of transcription terminator ter_rrnB. This fragment was obtained by PCR amplification of the corresponding region of Escherichia coli MG1655 chromosome using primers P7 and P8 (SEQ ID NOs: 37 and 38). These primers contain secondary recognition sites for Pstl and Bglll and Pstl.
  • pML-MCS plasmid (Mashko, SV et al., Biotekhnologiya (in Russian), 2001, no. 5, 3-20) is digested with Xbal and BamHI, then the large fragment (3342 bp) containing the ter_thrL terminator Ligated with Xbal-BamHI fragment (68bp).
  • a fragment containing this ter_thrL terminator was obtained by PCR using primers P9 and P10 (SEQ ID NOs: 40 and 41) in the corresponding region of Escherichia coli MG1655 chromosome. In this way, pML-ter_thrL plasmid was obtained. These primers contain secondary recognition sites for Pstl and Xbal and BamHI! / ⁇
  • pML-ter_thrL plasmid was digested with Kpnl and Xbal, then treated with DNA polymerase I Klenow fragment and ligated with pBR322 EcoR to Van91I small fragment (1317bp) with tetracycline resistance gene to obtain pML-Tc_ter_thrL plasmid .
  • PBR322 was digested with EcoRI and Van91I and then treated with DNA polymerase I Klenow fragment.
  • Plasmid RSFPPG was constructed by amplifying the L-glutamic acid biosynthesis gene, prpC gene (International Publication No. 2006/051660, pamphlet), ppc gene, and gdh (European Application Publication No. 0999282).
  • Primer 1 SEQ ID NO: 42
  • primer 2 SEQ ID NO: 43
  • PCR was carried out using RSFCPG in a cage shape to obtain a fragment of about 14.9 kb.
  • PCR was performed using primer 3 (SEQ ID NO: 44) and primer 4 (SEQ ID NO: 45), using the chromosomal DNA of Ecoli W3110 strain as a saddle to obtain a fragment of about 1.2 kb.
  • E. coli ME8330 a citrate synthase (CS) deficient strain, was transformed with this plasmid mixture, and M9 minimal medium (glucose 5 g, magnesium sulfate) containing 50 mg / L uracil, 5 mg / L thiamine-HC1 was transformed.
  • M9 minimal medium glucose 5 g, magnesium sulfate
  • 2 mM monopotassium phosphate 3 g, sodium chloride 0.5 g, ammonium chloride lg phosphate disodium 6 g in a medium containing 1 L of pure water.
  • a plasmid was extracted from the emerging strain and designated RSFPPG.
  • the plasmid RSFPPG was introduced into Pantoea ananatis NP106 strain, which is an L-glutamic acid-producing bacterium, to construct an L-glutamic acid-producing NP106 / RSFPPG (this strain is referred to as “NA Zhu”).
  • the NP106 strain was obtained as follows. Pantoea Ananatis AJ1 360 Zhu exemplified above is cultured overnight in LBGM9 liquid medium at 34 ° C, diluted to 100-200 colonies per plate, and LBGM9 plate containing tetracycline 12.5mg / L We applied to. The colonies that emerged were replicated on an LBGM9 plate containing tetracycline 12.5 mg / L and chloramphenicol 25 mg / L, and a strain that became chloramphenicol sensitive was selected, and a strain from which pSTVCB had dropped was obtained and named G106S. did.
  • the G106S strain was cultured with shaking in LBGM9 liquid medium at 34 ° C overnight, diluted to 100 to 200 colonies per plate, and applied to an LBGM9 plate containing no drug. The colonies that emerged were replicated on LBGM9 plates containing tetracycline 12.5mg / L and LBGM9 plates containing no drugs. Tetracycline-sensitive strains were selected, and a strain with RSFCPG S deletion was obtained and named NP106. .
  • the NP106 strain thus obtained is a strain that does not have both the two plasmids RSFCPG and pSTVCB carried by AJ1360 Zhu.
  • SC17 (0) was transformed with RSF-Red-TER to obtain SC17 (0) / RSF-Red_TER strain.
  • the same strain is cultured overnight in L medium containing 25 mg / L chloramphenicol (medium containing 10 g of Batatotryptone, 5 g of yeast extract, and 5 g of NaCl in 1 L of pure water, ⁇ ⁇ 7.0).
  • L medium containing 25 mg / L chloramphenicol (medium containing 10 g of Batatotryptone, 5 g of yeast extract, and 5 g of NaCl in 1 L of pure water, ⁇ ⁇ 7.0).
  • a 1/100 amount of LOOmL L medium containing 25mg / L chloramphenicol and ImM isopropyl- / 3_D_tiogalatatoviranoside was inoculated and cultured at 34 ° C for 3 hours.
  • the cells prepared in this way are collected, washed 3 times with ice-cold 10% glycerol, and finally suspended in 0.5 mL of 10% glycerol as a competent cell.
  • Fragment 1 OOng was introduced using GENE PULSER II (BioRad) under the conditions of an electric field strength of 18 kV, a capacitor capacity of 25 F, and a resistance of 200 ⁇ .
  • To the cell suspension add ice-cold SOC medium (batatryptone 20 g / L, yeast extratate 5 g / L, NaCl 0.5 g / L, glucose 10 g / L) at 34 ° C.
  • Chromosomes were extracted from this sdhA gene-deficient strain using Edge Biosystems Bacterial Genomic DNA Purification Kit.
  • the NAI strain was cultured overnight in an agar medium in which the above-mentioned minimum medium components and 12.5 mg / L tetracycline were added to L medium.
  • the cells are scraped with ase, washed with ice-cooled 10% glycerol three times, and 10% glycerol is added to the cells to a final volume of 500 ⁇ L and suspended. A cell.
  • 600 ng of the chromosomal DNA described above was introduced into this complex cell under conditions of an electric field strength of 17.5 kV, a capacitor capacity of 25 F, and a resistance value of 200 ⁇ using GENE PULSER II (BioRad).
  • GENE PULSER II BioRad
  • NA Zhu lacks the sucA gene that encodes the El subunit of ⁇ -KGDH.
  • the sucA gene of SC17 (0) / RSF-Red_TER strain has no mutation.
  • the sdhA gene and the sucA gene are very close together, and when the sdhA gene-deficient strain is transformed with chromosomal DNA, the wild-type sucA gene is also transferred at a certain rate along with the sdhA mutation. Therefore, two types of NA1 sdhA-deficient strains obtained include those that are deficient in the sucA gene and those that have reverted to the wild type.
  • the region corresponding to the mutation site of NA1's sucA gene is amplified by PCR, and the ability of sucA gene is restored or the sucA gene returns to the wild type, using as an index whether or not it can be cleaved by restriction enzyme Bglll.
  • restriction enzyme Bglll restriction enzyme
  • sucAsdhA double-deficient strains were inoculated into a test tube into which 5 mL of the medium having the composition shown below was injected, Culture was performed for 18 hours. NA Zhu, a sucA single-deficient strain, hardly grew on the same medium, and L-glutamic acid accumulation remained at about 3.3 g / L, whereas sdhA-deficient strain obtained 13.2 g / L L-glutamic acid accumulation. The result was much higher than that of the sucA single-deficient strain.
  • sucAsdhA double-deficient strains can accumulate 14.7 g / L of L-glutamate, have higher L-glutamate production capacity than sucA and sdhA deficient each, and greatly improve growth. Was confirmed.
  • Yeast Extract (Difco) 2g / L Canorescium pantothenate 18mg / L
  • Brevibacterium flavum ATCC 14067 strain from (currently (or Corynebacterium glutamicum ⁇ this minute), lacking odhA gene and is replaced with 837 of the G force S A of yggB gene (SEQ ID NO: 56), promoters of gdh gene
  • the ability to use ⁇ ⁇ ⁇ flavum ATCC14067 as the parent strain was the same as that of C. glutamicum ATCC1303 2 and lact ⁇ lactofermentum ATCC13869 as the parent strain. Strains can be constructed.
  • a plasmid pBS3 A sucA47 for deleting odhA was constructed. PCR was performed using the synthetic DNA shown in SEQ ID NO: 48 and the synthetic DNA shown in SEQ ID NO: 49 as primers and the chromosomal DNA of B. flavum ATCC1 4067 strain as a saddle to prepare an N-terminal fragment. Similarly, a C-terminal fragment was prepared using the synthetic DNAs of SEQ ID NO: 50 and SEQ ID NO: 51 as primers.
  • PCR was performed using a mixture of equal amounts of N-terminal fragment and C-terminal fragment as a cage, and using the synthetic DNAs of SEQ ID NO: 52 and SEQ ID NO: 53 (with a BamH sequence) added as primers, A fragment lacking the coding region of the odhA gene was obtained.
  • the obtained mutant odhA fragment was treated with BamHI and placed at the BamHI site of pBS3 (International Publication 2006/070944 pamphlet).
  • the obtained plasmid was designated as pBS3 ⁇ sucA47.
  • CM-Dex agar medium (glucose 5 g / l, polypeptone 10 g / l, yeast extract 10 g / l) containing pBS3 ⁇ sucA47 in ⁇ ⁇ ⁇ ⁇ flavum ATCC14067 and kanamycin 25 5 g / ml by electric pulse method , H PO lg / l, MgSO ⁇ 7 ⁇ ⁇ 0.4g / l, FeSO ⁇ 7 ⁇ ⁇ 0.01g / U MnSO ⁇ 4— 5 ⁇ ⁇ 0
  • a suspension of ATCC14067-pBS3 ⁇ sucA strain cultured overnight in CM_Dex liquid medium was added to a suspension of S 10 agar (sucrose 100 g / l, polypeptone 10 g / l, yeast extract 10 g / l, KH PO lg / 1
  • a strain showing kanamycin sensitivity was selected and further purified on a CM-Dex agar medium.
  • Chromosome DNA was prepared from these strains, and PCR was performed using the synthetic DNAs shown in SEQ ID NO: 52 and SEQ ID NO: 53 as primers, and a strain in which an amplified fragment of about 1.9 Kb was confirmed was designated as 8L3 strain.
  • PCR was performed using the chromosomal DNA of strain 8L3 as a saddle and the synthetic DNAs of SEQ ID NO: 54 and SEQ ID NO: 55 (added with Sad sequence) as primers.
  • sequence of the amplified fragment was determined, it was shown that the alanine at position 111 of SEQ ID NO: 57 was replaced with threonine!
  • 8L3 was a double mutant in which this mutation was accidentally introduced when odhA deficiency was introduced.
  • the ATCC14067yggB8 strain is known as a strain having the same yggB mutation as 8L3 (International Publication 2006/070944 Pamphlet).
  • a plasmid pBS4gdh3 for introducing a mutation into the promoter region of gdh was constructed.
  • PCR was performed using the chromosomal DNA of B. lactofermentum ATCC13869 strain as a saddle to prepare an N-terminal fragment.
  • a C-terminal fragment was prepared using the synthetic DNAs of SEQ ID NO: 62 and SEQ ID NO: 63 as primers. Next, mix the same amount of N-terminal fragment and C-terminal fragment.
  • PCR was performed using the synthetic DNAs of SEQ ID NO: 64 and SEQ ID NO: 65 (with Smd sequence added) as primers to obtain fragments in which mutations were introduced into the promoter region of the gdh gene.
  • the obtained mutant gdh fragment was treated with Smal and inserted into the Smal site of pBS4S (International Publication 2006/070 944 pamphlet), and the resulting plasmid was designated as pBS4gdh3.
  • pBS4gdh3 was introduced into the 8L3 strain by an electric pulse method, and applied to a CM-Dex agar medium containing 25 ⁇ g / ml kanamycin. After culturing at 31.5 ° C for 3 days, the growing strain was isolated as strain 8L3_pBS4gdh3 in which pBS4gdh3 was inserted into the chromosome. Next, a suspension of 8L3_pBS4gdh3 strain cultured overnight in CM-Dex liquid medium was spread on S10 agar medium and cultured at 31.5 ° C. Among the appearing colonies, a strain showing kanamycin sensitivity was selected and further purified on CM-Dex agar medium. Chromosomal DNA was prepared from these strains, and the sequence upstream of the gdh coding region was determined. The strain having the sequence shown in SEQ ID NO: 66 was designated as 8L3G strain.
  • Plasmid pBS3 A sdh47 for deletion of sdhA was constructed. PCR was carried out using the synthetic DNA shown in SEQ ID NO: 67 and the synthetic DNA shown in SEQ ID NO: 68 as primers and the chromosomal DNA of B. flavum ATCC14067 strain as a saddle to prepare an N-terminal fragment. Similarly, a C-terminal fragment was prepared using the synthetic DNAs of SEQ ID NO: 69 and SEQ ID NO: 70 as primers.
  • PCR was carried out using a mixture of equal amounts of N-terminal fragment and C-terminal fragment as a saddle type, and using the synthetic DNAs of SEQ ID NO: 71 and SEQ ID NO: 72 as primers, and the coding region of the sdhA gene was deleted. A fragment was obtained.
  • the obtained mutant sdhA fragment was treated with B ⁇ HI and inserted into the BamHI site of pBS3 (International Publication No. 2006/070944 Pamphlet), and the resulting plasmid was designated as pBS3 ⁇ sdhA47.
  • pBS3 ⁇ sdhA47 was introduced into the 8L3G strain by an electric pulse method, and applied to a CM-Dex agar medium containing 25 ⁇ g / ml of kanamycin. After culturing at 31.5 ° C for 2 days, the growing strain was isolated as strain 8L3G_pBS3 ⁇ sdhA in which pBS 3 ⁇ sdhA47 was inserted into the chromosome. Then, a suspension of 8L3 G-pBS3 ⁇ sdhA strain cultured overnight in CM-Dex liquid medium was applied onto S10 agar medium and cultured at 31.5 ° C.
  • a strain showing kanamycin sensitivity was selected and further purified on CM-Dex agar medium. Chromosomal DNA is prepared from these strains, and the synthetic DNA shown in SEQ ID NO: 71 and SEQ ID NO: 72 (with B ⁇ M sequence added) is applied. A strain in which an amplified fragment of about 1 Kb was confirmed by PCR was used as an 8L3G A SDH strain.
  • each of these strains was placed on one CM-Dex plate medium. After cell culture, all of the cells were scraped from the plate, inoculated into a jar injected with 300 mL of the medium having the composition shown below, and cultured at 31.5 ° C. The pH during the culture was controlled to 7.2 using ammonia gas, and aeration and agitation were controlled so that the dissolved oxygen concentration was maintained at 5% or higher.
  • L glutamate accumulation at 12.5 hours in culture is higher in 8L3G A SDH, which is a sucAsdhA double-deficient strain than in 8L3G strain, which is a single sucA-deficient strain.
  • the 8L3G A SDH strain was 16.5 g / L, while the 8L3G ⁇ SDH strain was 19 g / L, a result much higher than the 8L3G strain, which is a sucA-deficient strain. From these results, it was shown that it is effective in L-glutamic acid production to simultaneously delete sucA and sdhA in coryneform bacteria.
  • Adjust to pH 4.0 with aqueous ammonia sterilize at 120 ° C for 15 minutes, and adjust to pH 7.2 with ammonia gas immediately before cultivation.
  • SEQ ID NO: 1 Pantoea 'Ananatis sdh operon nucleotide sequence (SDHD, SDHA, SDH B amino acid sequence shown together)
  • SEQ ID NO: 2 Amino acid arrangement of SDHD IJ
  • SEQ ID NO: 3 amino acid sequence of SDHA
  • SEQ ID NO: 4 SDHB amino acid sequence IJ
  • SEQ ID NO: 5 Pantoea Ananatis sdh operon nucleotide sequence (SDHC amino acid sequence)
  • SEQ ID NO: 7 Base sequence of Pantoea ananatis ⁇ - KGDH subunit gene and neighboring genes
  • SEQ ID NO: 8 Amino acid sequence (part) of succinate dehydrogenase ironsulfur protein
  • SEQ ID NO: 9 Amino acid sequence of ⁇ -KGDH Elo subunit
  • SEQ ID NO: 10 amino acid sequence of ⁇ -KGDH E2o subunit
  • SEQ ID NO: 11 part of succinyl-CoA synthetase ⁇ subunit
  • SEQ ID NO: 12 Nucleotide sequence of odhA gene of Brevipacterum ratatofarmentum
  • SEQ ID NO: 13 Amino acid sequence of Elo subunit encoded by odhA
  • SEQ ID NO: 14 Nucleotide sequence of the gene (NCgl2126 of GenBank Accession No. NC 003450) encoding the E2o subunit of Brevibateratum 'Ratatomentumum
  • SEQ ID NO: 15 Amino acid sequence of E2o subunit encoded by NCgl2126
  • SEQ ID NO: 16 Pantoea ananatis hisD gene base sequence
  • SEQ ID NO: 17 Primer for amplification of fragment for integration of Km f gene into hisD gene
  • SEQ ID NO: 18 Primer for amplification of fragment for integration of Km f gene into hisD gene
  • SEQ ID NO: 19 For amplification of cat gene Primer
  • SEQ ID NO: 20 Primer for cat gene amplification
  • SEQ ID NO: 21 primer for amplifying sacB gene
  • SEQ ID NO: 22 primer for amplifying sacB gene
  • SEQ ID NO: 23 Primer for DNA fragment amplification containing P promoter
  • SEQ ID NO: 24 Primer for amplifying DNA fragment containing P promoter
  • SEQ ID NO: 25 Primer for amplification of DNA fragment containing Red a ⁇ gene and tL3 SEQ ID NO: 26: Primer for amplification of DNA fragment containing Red a ⁇ gene and tL3 SEQ ID NO: 27: For amplification of DNA fragment containing P promoter and TrmB Primer
  • SEQ ID NO 2 8 P promoter and DNA fragment amplification primer comprising TrmB
  • SEQ ID NO: 29 attL amplification primer
  • SEQ ID NO: 30 primer for attL amplification
  • SEQ ID NO: 31 nucleotide sequence of attL
  • SEQ ID NO: 32 primer for attR amplification
  • SEQ ID NO: 33 primer for attR amplification
  • SEQ ID NO: 34 nucleotide sequence of attR
  • SEQ ID NO: 35 Primer for DNA fragment amplification containing bla gene
  • SEQ ID NO: 36 Primer for DNA fragment amplification containing bla gene
  • SEQ ID NO: 37 DNA fragment amplification primer containing ter_rrnB
  • SEQ ID NO: 38 DNA fragment amplification primer containing ter_rrnB
  • SEQ ID NO: 39 Base sequence of DNA fragment containing ter_thrL terminator SEQ ID NO: 40: Primer for DNA fragment amplification containing ter_thrL terminator SEQ ID NO: 41: Primer for DNA fragment amplification containing ter_thrL terminator SEQ ID NO: 42: ORF of gltA gene Primer for amplifying the other part SEQ ID NO: 43: Primer for amplifying the part other than the ORF of the gltA gene SEQ ID NO: 44: Primer for prpC gene amplification
  • SEQ ID NO: 45 primer for prpC gene amplification
  • SEQ ID NO: 46 DNA fragment amplification primer for sdhA disruption
  • SEQ ID NO: 47 DNA fragment amplification primer for sdhA disruption
  • SEQ ID NO: 48 primer for amplifying sucA gene upstream fragment
  • SEQ ID NO: 49 Primer for amplification of sucA gene upstream fragment
  • SEQ ID NO: 50 primer for amplifying downstream fragment of sucA gene
  • SEQ ID NO: 51 Primer for amplification of sucA gene downstream fragment
  • SEQ ID NO: 52 primer for amplifying sucA gene
  • SEQ ID NO: 53 primer for amplifying sucA gene
  • SEQ ID NO: 54 yggB gene amplification primer
  • SEQ ID NO: 55 primer for yggB gene amplification
  • SEQ ID NO: 56 base sequence of yggB gene
  • SEQ ID NO: 57 Amino acid sequence of YggB
  • SEQ ID NO: 58 Nucleotide sequence of mutant yggB gene
  • SEQ ID NO: 59 Amino acid sequence of mutant YggB
  • SEQ ID NO: 60 primer for upstream amplification of gdh gene (mutation introduction)
  • SEQ ID NO: 61 primer for upstream amplification of gdh gene
  • SEQ ID NO: 62 primer for downstream amplification of gdh gene
  • SEQ ID NO: 63 primer for downstream amplification of gdh gene (mutation introduction)
  • SEQ ID NO: 64 primer for amplifying gdh gene
  • SEQ ID NO: 65 primer for amplifying gdh gene
  • SEQ ID NO: 66 nucleotide sequence upstream of the mutant gdh gene coding region
  • SEQ ID NO: 67 primer for upstream amplification of sdhA gene
  • SEQ ID NO: 68 primer for upstream amplification of sdhA gene (mutation introduction)
  • SEQ ID NO: 69 primer for downstream amplification of sdhA gene
  • SEQ ID NO: 70 primer for downstream amplification of sdhA gene (mutation introduction)
  • SEQ ID NO: 71 primer for amplifying sdhA gene
  • SEQ ID NO: 72 primer for amplifying sdhA gene
  • SEQ ID NO: 73 nucleotide sequence of sdh operon of C. glutamicum ATCC13032 (along with amino acid sequences of SDHC, SDHA, SDHB)
  • SEQ ID NO: 74 amino acid arrangement of SDHC IJ
  • SEQ ID NO: 75 Amino acid sequence of SDHA
  • SEQ ID NO: 76 amino acid arrangement of SDAB IJ
  • SEQ ID NO: 77 base sequence of sdh operon of B. lactofermentum ATCC13869 (along with amino acid sequences of SDHC, SD HA, SDHB)
  • SEQ ID NO: 78 SDHC amino acid sequence IJ
  • SEQ ID NO: 79 Amino acid sequence of SDHA
  • SEQ ID NO: 80 SDHB amino acid sequence IJ
  • L-amino acids such as L-glutamic acid can be fermented and produced efficiently.
PCT/JP2007/067387 2006-12-19 2007-09-06 Ｌ－アミノ酸の製造法 WO2008075483A1 (ja)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP07806828.5A EP2100957B1 (en) 2006-12-19 2007-09-06 Process for production of l-glutamic acid
BRPI0721063-9A BRPI0721063B1 (pt) 2006-12-19 2007-09-06 Method for producing an l-aminoacid
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